Skip to main content

Advertisement

SpringerLink
Log in

Analysis of GJB2 mutations and the clinical manifestation in a large Hungarian cohort

  • Otology
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Purpose

Pathogenic variants of the gap junction beta 2 (GJB2) gene are responsible for about 50% of hereditary non-syndromic sensorineural hearing loss (NSHL). In this study, we report mutation frequency and phenotype comparison of different GJB2 gene alterations in Hungarian NSHL patients.

Methods

The total coding region of the GJB2 gene was analyzed with Sanger or NGS sequencing for 239 patients with NSHL and 160 controls.

Results

Homozygous and compound heterozygous GJB2 mutations were associated with early onset serious clinical phenotype in 28 patients. In 24 patients, two deletion or nonsense mutations were detected in individuals with mainly prelingual NSHL. In compound heterozygous cases, a combination of deletion and missense mutations associated with milder postlingual NSHL. A further 25 cases harbored single heterozygous GJB2 mutations mainly associated with later onset, milder clinical phenotype. The most common mutation was the c.35delG deletion, with 12.6% allele frequency. The hearing loss was more severe in the prelingual groups.

Conclusion

The mutation frequency of GJB2 in the investigated cohort is lower than in other European cohorts. The most serious cases were associated with homozygous and compound heterozygous mutations. In our cohort the hearing impairment and age of onset was not altered between in cases with only one heterozygous GJB2 mutation and wild type genotype, which may exclude the possibility of autosomal dominant inheritance. In early onset, severe to profound hearing loss cases, if the GJB2 analysis results in only one heterozygous alteration further next generation sequencing is highly recommended.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Morton CC, Nance WE (2006) Newborn hearing screening—a silent revolution. N Engl J Med 354(20):2151–2164. https://doi.org/10.1056/NEJMra050700

    Article  PubMed  CAS  Google Scholar 

  2. Lazar C, Popp R, Trifa A, Mocanu C, Mihut G, Al-Khzouz C, Tomescu E, Figan I, Grigorescu-Sido P (2010) Prevalence of the c.35delG and p.W24X mutations in the GJB2 gene in patients with nonsyndromic hearing loss from North-West Romania. Int J Pediatr Otorhinolaryngol 74:351–355

    Article  PubMed  CAS  Google Scholar 

  3. Denoyelle F, Weil D, Maw MA, Wilcox SA, Lench NJ, Allen-Powell DR, Osborn AH, Dahl HH, Middleton A, Houseman MJ, Dodé C, Marlin S, Boulila-ElGaïed A, Grati M, Ayadi H, BenArab S, Bitoun P, Lina-Granade G, Godet J, Mustapha M, Loiselet J, El-Zir E, Aubois A, Joannard A, Levilliers J, Garabédian EN, Mueller RF, Gardner RJ, Petit C (1997) Prelingual deafness: high prevalence of a 30delG mutation in the connexin 26 gene. Hum Mol Genet 6(12):2173–2177

    Article  PubMed  CAS  Google Scholar 

  4. Lilly E, Sellitto C, Milstone LM, White TW (2016) Connexin channels in congenital skin disorders. Semin Cell Dev Biol 50:4–12. https://doi.org/10.1016/j.semcdb.2015.11.018

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Milley GM, Varga ET, Grosz Z, Bereznai B, Aranyi Z, Boczan J, Dioszeghy P, Kálmán B, Gal A, Molnar MJ (2016) Three novel mutations and genetic epidemiology analysis of the Gap Junction Beta 1 (GJB1) gene among Hungarian Charcot–Marie–Tooth disease patients. Neuromuscul Disord 26(10):706–711. https://doi.org/10.1016/j.nmd.2016.07.012

    Article  PubMed  Google Scholar 

  6. Dános K, Brauswetter D, Birtalan E, Pató A, Bencsik G, Krenács T, Peták I, Tamás L (2016) The potential prognostic value of connexin 43 expression in head and neck squamous cell carcinomas. Appl Immunohistochem Mol Morphol 24(7):476–481. https://doi.org/10.1097/PAI.0000000000000212

    Article  PubMed  CAS  Google Scholar 

  7. Martínez AD, Acuña R, Figueroa V, Maripillan J, Nicholson B (2009) Gap-junction channels dysfunction in deafness and hearing loss. Antioxid Redox Signal 11(2):309–322. https://doi.org/10.1089/ars.2008.2138

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. The connexin-deafness homepage. http://davinci.crg.es/deafness/. Accessed Aug 2018

  9. Gasparini P, Rabionet R, Barbujani G, Melçhionda S, Petersen M, Brøndum-Nielsen K, Metspalu A, Oitmaa E, Pisano M, Fortina P, Zelante L, Estivill X (2000) High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. Eur J Hum Genet 8(1):19–23. https://doi.org/10.1038/sj.ejhg.5200406

    Article  PubMed  CAS  Google Scholar 

  10. Clark JG (1981) Uses and abuses of hearing loss classification. ASHA 23(7):493–500

    PubMed  CAS  Google Scholar 

  11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 17(5):405–424. https://doi.org/10.1038/gim.2015.30

  12. Chan DK, Chang KW (2014) GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope 124(2):E34–E53. https://doi.org/10.1002/lary.24332

    Article  PubMed  Google Scholar 

  13. Bors A, Andrikovics H, Kalmar L, Erdei N, Galambos S, Losonczi A, Furedi S, Balogh I, Szalai C, Tordai A (2004) Frequencies of two common mutations (c.35delG and c.l67delT) of the connexin 26 gene in different populations of Hungary. Int J Mol Med 14:1105–1108

    PubMed  CAS  Google Scholar 

  14. Dai P, Yu F, Han B, Liu X, Wang G, Li Q, Yuan Y, Huang D, Kang D, Zhang X, Yuan H, Yao K, Hao J, He J, He Y, Wang Y, Ye Q, Yu Y, Lin H, Liu L, Deng W, Zhu X, You Y, Cui J, Hou N, Xu X, Zhang J, Tang L, Song R, Lin Y, Sun S, Zhang R, Wu H, Ma Y, Zhu S, Wu BL, Han D, Wong LJ (2009) GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. J Transl Med 7:26. https://doi.org/10.1186/1479-5876-7-26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Marlin S, Feldmann D, Blons H, Loundon N, Rouillon I, Albert S, Chauvin P, Garabédian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Lemarechal C, Dollfus H, Eliot MM, Delaunoy JL, David A, Calais C, Drouin-Garraud V, Obstoy MF, Goizet C, Duriez F, Fellmann F, Hélias J, Vigneron J, Montaut B, Matin-Coignard D, Faivre L, Baumann C, Lewin P, Petit C, Denoyelle F (2005) GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg 131(6):481–487. https://doi.org/10.1001/archotol.131.6.481

    Article  PubMed  Google Scholar 

  16. Cryns K, Orzan E, Murgia A, Huygen PL, Moreno F, del Castillo I, Chamberlin GP, Azaiez H, Prasad S, Cucci RA, Leonardi E, Snoeckx RL, Govaerts PJ, Van de Heyning PH, Van de Heyning CM, Smith RJ, Van Camp G (2004) A genotype-phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet 41(3):147–154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Tekin M, Duman T, Boğoçlu G, Incesulu A, Cin S, Akar N (2003) Moderate hearing loss and pseudodominant inheritance due to L90P/35delG mutations in the GJB2 (connexin 26) gene. Genet Couns 14(4):379–386

    PubMed  CAS  Google Scholar 

  18. Pittman AL, Stelmachowicz PG (2003) Hearing loss in children and adults: audiometric configuration, asymmetry, and progression. Ear Hear 24(3):198–205. https://doi.org/10.1097/01.AUD.0000069226.22983.80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hoffman HJ, Dobie RA, Losonczy KG, Themann CL, Flamme GA (2017) Declining prevalence of hearing loss in US adults aged 20 to 69 years. JAMA Otolaryngol Head Neck Surg 143(3):274–285. https://doi.org/10.1001/jamaoto.2016.3527

    Article  PubMed  PubMed Central  Google Scholar 

  20. Homans NC, Metselaar RM, Dingemanse JG, van der Schroeff MP, Brocaar MP, Wieringa MH, Baatenburg de Jong RJ, Hofman A, Goedegebure A (2017) Prevalence of age-related hearing loss, including sex differences, in older adults in a large cohort study. Laryngoscope 127(3):725–730. https://doi.org/10.1002/lary.26150

    Article  PubMed  Google Scholar 

  21. Zelante L, Gasparini P, Estivill X, Melchionda S, D’Agruma L, Govea N, Milá M, Monica MD, Lutfi J, Shohat M, Mansfield E, Delgrosso K, Rappaport E, Surrey S, Fortina P (1997) Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 6(9):1605–1609

    Article  PubMed  CAS  Google Scholar 

  22. Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM (1997) Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387(6628):80–83. https://doi.org/10.1038/387080a0

    Article  PubMed  CAS  Google Scholar 

  23. Feldmann D, Denoyelle F, Loundon N, Weil D, Garabedian EN, Couderc R, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Ferrec C, Drouin-Garraud V, Obstoy MF, Moati L, Petit C, Marlin S (2004) Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene. Eur J Hum Genet 12(4):279–284. https://doi.org/10.1038/sj.ejhg.5201147

    Article  PubMed  CAS  Google Scholar 

  24. Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ (1998) Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet 62(4):792–799. https://doi.org/10.1086/301807

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Snoeckx RL, Huygen PL, Feldmann D, Marlin S, Denoyelle F, Waligora J, Mueller-Malesinska M, Pollak A, Ploski R, Murgia A, Orzan E, Castorina P, Ambrosetti U, Nowakowska-Szyrwinska E, Bal J, Wiszniewski W, Janecke AR, Nekahm-Heis D, Seeman P, Bendova O, Kenna MA, Frangulov A, Rehm HL, Tekin M, Incesulu A, Dahl HH, du Sart D, Jenkins L, Lucas D, Bitner-Glindzicz M, Avraham KB, Brownstein Z, del Castillo I, Moreno F, Blin N, Pfister M, Sziklai I, Toth T, Kelley PM, Cohn ES, Van Maldergem L, Hilbert P, Roux AF, Mondain M, Hoefsloot LH, Cremers CW, Löppönen T, Löppönen H, Parving A, Gronskov K, Schrijver I, Roberson J, Gualandi F, Martini A, Lina-Granade G, Pallares-Ruiz N, Correia C, Fialho G, Cryns K, Hilgert N, Van de Heyning P, Nishimura CJ, Smith RJ, Van Camp G (2005) GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet 77(6):945–957. https://doi.org/10.1086/497996

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Murgia A, Orzan E, Polli R, Martella M, Vinanzi C, Leonardi E, Arslan E, Zacchello F (1999) Cx26 deafness: mutation analysis and clinical variability. J Med Genet 36(11):829–832

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Frei K, Lucas T, Ramsebner R, Schöfer C, Baumgartner WD, Weipoltshammer K, Erginel-Unaltuna N, Wachtler FJ, Kirschhofer K (2004) A novel connexin 26 mutation associated with autosomal recessive sensorineural deafness. Audiol Neurootol 9(1):47–50. https://doi.org/10.1159/000074186

    Article  PubMed  CAS  Google Scholar 

  28. Zoll B, Petersen L, Lange K et al (2003) Evaluation of Cx26/GJB2 in german hearing impaired persons: mutation spectrum and detection of disequilibrium between M34T (c.101T>C) and -493del10. Hum Mutat 21(1):98. https://doi.org/10.1002/humu.9098

    Article  PubMed  CAS  Google Scholar 

  29. Minárik G, Tretinárová D, Szemes T, Kádasi L (2012) Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss. Int J Pediatr Otorhinolaryngol 76(3):400–403. https://doi.org/10.1016/j.ijporl.2011.12.020

    Article  PubMed  Google Scholar 

  30. Medica I, Rudolf G, Balaban M, Peterlin B (2005) C.35delG/GJB2 and del(GJB6-D13S1830) mutations in Croatians with prelingual non-syndromic hearing impairment. BMC Ear Nose Throat Disord 5:11. https://doi.org/10.1186/1472-6815-5-11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Seeman P, Malíková M, Rasková D, Bendová O, Groh D, Kubálková M, Sakmaryová I, Seemanová E, Kabelka Z (2004) Spectrum and frequencies of mutations in the GJB2 (Cx26) gene among 156 Czech patients with pre-lingual deafness. Clin Genet 66(2):152–157. https://doi.org/10.1111/j.1399-0004.2004.00283.x

    Article  PubMed  CAS  Google Scholar 

  32. Popova DP, Kaneva R, Varbanova S, Popov TM (2012) Prevalence of GBJ2 mutations in patients with severe to profound congenital nonsyndromic sensorineural hearing loss in Bulgarian population. Eur Arch Otorhinolaryngol 269(6):1589–1592. https://doi.org/10.1007/s00405-011-1817-2

    Article  PubMed  Google Scholar 

  33. Danilenko N, Nina Danilenko EM, Siniauskaya MO, Levaya-Smaliak O, Alena Kushniarevich A, Shymkevich A, Davydenko A A (2012) Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutations in Belarus. PLoS One 7(5):e36354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to the patients and their clinicians for providing samples. The authors would like to thank Györgyi Báthori, Margit Kovács, Tunde Szosznyak, and Gabriella Porpaczy for their technical help and Lisa Hubers for language revision.

Funding

This study was supported by the Hungarian Brain Research Program (KTIA_13_NAP-A-III/6).

Author information

Author notes

  1. Nóra Kecskeméti, Magdolna Szönyi, Ágnes Szirmai, and Anikó Gál contributed equally to this work.

Authors and Affiliations

  1. Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Tömö utca 25-29, Budapest, 1083, Hungary

    Nóra Kecskeméti, György Máté Milley, Anna Süveges, Anett Illés, Anna Kékesi, Mária Judit Molnár & Anikó Gál

  2. Department of Otorhinolaryngology, Head and Neck Surgery, Semmelweis University, Szigony utca 36, Budapest, 1083, Hungary

    Nóra Kecskeméti, Magdolna Szönyi, Anita Gáborján, Marianna Küstel, László Tamás & Ágnes Szirmai

Authors
  1. Nóra Kecskeméti
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdolna Szönyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anita Gáborján
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marianna Küstel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. György Máté Milley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Süveges
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anett Illés
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anna Kékesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. László Tamás
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mária Judit Molnár
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ágnes Szirmai
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anikó Gál
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anikó Gál.

Ethics declarations

Conflict of interest

All the authors declare that they have no conflict of interest.

Ethical standards

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The procedures were conducted in accordance with the Hungarian Humangenetic law.

Informed consent

Written informed consents were obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kecskeméti, N., Szönyi, M., Gáborján, A. et al. Analysis of GJB2 mutations and the clinical manifestation in a large Hungarian cohort. Eur Arch Otorhinolaryngol 275, 2441–2448 (2018). https://doi.org/10.1007/s00405-018-5083-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-018-5083-4

Keywords

Search

Navigation